The major goal of this research project is to determine the fundamental mechanisms of autoimmune disease and malignant lymphomas that develop spontaneously in autoimmune NZB mice and their crosses with the normal SWR mice. The NZB x SWR crosses have not only proved useful to dissect the role of various abnormalities of the NZB strain in the etiology of autoimmune disease, but are also helping us to identify the factors contributed by a normal strain in the development of lupus nephritis.
AIm ost 100% of (NZB x SWR) F1 mice rapidly develop a lethally severe glomerulonephritis, in marked contrast to their autoimmune NZB parents. Monoclonal anti-DNA autoantibodies derived from the F1 mice by hybridoma technology will be analyzed for their antigen-binding specificity patterns, spectrotypes and allotypes. The F1-derived autoantibodies that are encoded by genes inherited from the NZB parent and those that are encoded by antibody genes from the SWR parent will be identified. Anti-idiotypic antibodies specific for these autoantibodies will be raised. These reagents will be used to study the inheritance and regulation of expression of these autoantibody idiotypes and their relation to nephritis development in NZB x SWR crosses. These autoantibody idiotypes will be deliberately suppressed to prevent the development of nephritis. The major genes determining the development of autoimmune disease will be identified and mapped by constucting recombinant inbred and congenic lines of mice. Finally, to define the mechanism of lymphoid malignancy, the cellular origin of the NZB lymphomas will be determined. The genomic structure of viruses produced by the lymphomas will be analyzed by T1 oligonucleotide fingerprinting and restriction endonuclease mapping techniques. Rearrangement of retroviral genes and cellular oncogenes in the lymphomas will also be studied. (MI)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031789-11
Application #
3169906
Study Section
Immunobiology Study Section (IMB)
Project Start
1979-07-01
Project End
1992-04-30
Budget Start
1989-05-01
Budget End
1990-04-30
Support Year
11
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Datta, S K; Kaliyaperumal, A; Mohan, C et al. (1997) T helper cells driving pathogenic anti-DNA autoantibody production in lupus: nucleosomal epitopes and CD40 ligand signals. Lupus 6:333-6
Datta, S K; Kaliyaperumal, A; Desai-Mehta, A (1997) T cells of lupus and molecular targets for immunotherapy. J Clin Immunol 17:11-20
Desai-Mehta, A; Lu, L; Ramsey-Goldman, R et al. (1996) Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97:2063-73
Kaliyaperumal, A; Mohan, C; Wu, W et al. (1996) Nucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med 183:2459-69
Mohan, C; Datta, S K (1995) Lupus: key pathogenic mechanisms and contributing factors. Clin Immunol Immunopathol 77:209-20
Datta, S K; Mohan, C; Desai-Mehta, A (1995) Mechanisms of the pathogenic autoimmune response in lupus: prospects for specific immunotherapy. Immunol Res 14:132-47
Mohan, C; Shi, Y; Laman, J D et al. (1995) Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol 154:1470-80
Mao, C; Osman, G E; Adams, S et al. (1994) T cell receptor alpha-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice. J Immunol 152:1462-70
Mohan, C; Adams, S; Stanik, V et al. (1993) Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. J Exp Med 177:1367-81
O'Keefe, T L; Datta, S K; Imanishi-Kari, T (1992) Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily. Eur J Immunol 22:619-24

Showing the most recent 10 out of 26 publications